Efficacy and Safety Evaluation of Alectinib and Entrectinib Versus Durvalumab in Biomarker-Selected Stage III NSCLC Post-Chemoradiotherapy

The primary objective of this study is to evaluate the **efficacy** of the study treatments, alectinib or entrectinib, compared with durvalumab in patients with biomarker-selected, locally advanced, unresectable, Stage III Non-Small Cell Lung Cancer (NSCLC) who have received concurrent chemoradiotherapy (cCRT) or sequential chemoradiotherapy (sCRT) and have not experienced radiographic disease progression. The primary endpoint is progression-free survival (PFS), which is a critical measure of the time during and after treatment that a patient lives with the disease without it worsening. This is clinically relevant as it provides insight into the potential of these treatments to delay disease progression in this patient population.

Secondary objectives include: - Evaluating the efficacy of the study treatments compared with durvalumab in terms of time to central nervous system (CNS) progression, distant metastasis-free survival (DMFS), and objective response rate (ORR) as determined by blinded independent central review (BICR) per RECIST v1.1. Additionally, progression-free survival (PFS), duration of response (DOR), and overall survival (OS) will be assessed as determined by the investigator per RECIST v1.1. - Assessing the health-related quality of life of patients in the study treatment arm compared with those in the durvalumab arm. - Evaluating the safety and tolerability of the study treatments compared with durvalumab in the specified patient population.

The clinical trial involves a total of **293 participants** diagnosed with **Non-Small Cell Lung Cancer (NSCLC)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically documented locally advanced, unresectable Stage III NSCLC, and no disease progression during or following at least two cycles of platinum-based concurrent or sequential chemoradiotherapy. The trial includes individuals with documented ALK or ROS1 fusion positivity. The population is characterized by a mix of squamous and non-squamous histology, as per the American Joint Committee on Cancer/Union for International Cancer Control NSCLC staging system. The trial also considers vulnerable populations, ensuring a comprehensive evaluation of the study treatment's efficacy. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **efficacy** and safety of multiple therapies in patients with locally advanced, unresectable, Stage III **Non-Small Cell Lung Cancer (NSCLC)**. This is a Phase I-III, multicenter study that employs a randomized, double-blind, controlled trial design. The trial aims to compare the efficacy of **alectinib** or entrectinib with **durvalumab** in patients who have received concurrent or sequential chemoradiotherapy and have not experienced radiographic disease progression. The primary endpoint is progression-free survival (PFS), assessed by a blinded independent central review per RECIST v1.1. Secondary endpoints include time to central nervous system progression, distant metastasis-free survival, objective response rate, duration of response, overall survival, and patient-reported outcomes related to lung cancer symptoms.

The trial is expected to commence recruitment on January 18, 2024, and is estimated to conclude by September 1, 2033. Participants will be involved in the study for a maximum treatment period of 36 to 52 weeks, depending on the assigned therapy. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. Inclusion criteria require participants to have a histologically or cytologically confirmed diagnosis of locally advanced, unresectable Stage III NSCLC, with no disease progression after at least two cycles of platinum-based chemoradiotherapy. Participants must also have documented ALK or ROS1 fusion positivity, depending on the cohort.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study will adhere to rigorous safety monitoring, with adverse events classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. The trial will ensure that all investigational medicinal products are administered according to protocol specifications, with **alectinib** administered orally and **durvalumab** via intravenous infusion. The study's design and procedures are structured to provide comprehensive data on the comparative efficacy and safety of the investigational therapies in this patient population.

The clinical trial involves the administration of **Alecensa** (alectinib) 150 mg hard capsules, which is an experimental medication. Alecensa is formulated as hard capsules and is administered orally. The maximum daily dose is 1200 mg, with a total maximum dose of 1314 g over a treatment period of up to 36 months. Alecensa is a tyrosine kinase inhibitor, and its active substance, alectinib, is of chemical origin. The medication is provided by Roche Registration GmbH and is not a pediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the study.

In addition to Alecensa, the study also includes the administration of **IMFINZI** (durvalumab) 50 mg/mL concentrate for solution for infusion as a comparator treatment. IMFINZI is administered via intravenous infusion. The maximum daily dose is 1500 mg, with a total maximum dose of 19.5 g over a treatment period of up to 52 weeks. Durvalumab is a protein-based substance, specifically categorized as "Protein - Other," and is provided by AstraZeneca AB. This medication is also not a pediatric formulation. The administration of IMFINZI will be conducted under controlled conditions to ensure participant safety and adherence to the dosing regimen.

The efficacy of the clinical trial will be assessed primarily through **Progression-free survival (PFS)**, as determined by Blinded Independent Central Review (BICR) per RECIST v1.1. Secondary endpoints include several parameters: PFS defined as the time from randomization to the first documented disease progression or death from any cause, time to central nervous system (CNS) progression, distant metastasis-free survival (DMFS), objective response rate (ORR), duration of response (DOR), overall survival (OS), and time-to-confirmed deterioration (TTCD) in patient-reported scales and lung cancer symptoms. These symptoms include physical functioning, role functioning, cough, chest pain, and dyspnea. Additionally, changes from baseline scores will be measured using the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at 5, 11, and 17 months.

The incidence, type, and severity of adverse events will be recorded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Changes in vital signs, physical findings, and clinical laboratory results will also be monitored during and following the administration of protocol-specified investigational medicinal products (IMPs). The trial will involve patients with locally advanced, unresectable, Stage III Non-Small Cell Lung Cancer (NSCLC) who have received concurrent or sequential chemoradiotherapy and have not experienced radiographic disease progression. The study will compare the efficacy of alectinib or entrectinib with durvalumab in biomarker-selected patients.